Source:http://linkedlifedata.com/resource/pubmed/id/11753432
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2
|
| pubmed:dateCreated |
2002-1-28
|
| pubmed:databankReference | |
| pubmed:abstractText |
Mutations in domain 2 (D2, residues 151-266) of the actin-binding protein gelsolin cause familial amyloidosis-Finnish type (FAF). These mutations, D187N or D187Y, lead to abnormal proteolysis of plasma gelsolin at residues 172-173 and a second hydrolysis at residue 243, resulting in an amyloidogenic fragment. Here we present the structure of human gelsolin D2 at 1.65 A and find that Asp 187 is part of a Cd2+ metal-binding site. Two Ca2+ ions are required for a conformational transition of gelsolin to its active form. Differential scanning calorimetry (DSC) and molecular dynamics (MD) simulations suggest that the Cd2+-binding site in D2 is one of these two Ca2+-binding sites and is essential to the stability of D2. Mutation of Asp 187 to Asn disrupts Ca2+ binding in D2, leading to instabilities upon Ca2+ activation. These instabilities make the domain a target for aberrant proteolysis, thereby enacting the first step in the cascade leading to FAF.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Feb
|
| pubmed:issn |
1072-8368
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
9
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
112-6
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| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:11753432-Amino Acid Substitution,
pubmed-meshheading:11753432-Amyloidosis, Familial,
pubmed-meshheading:11753432-Aspartic Acid,
pubmed-meshheading:11753432-Binding Sites,
pubmed-meshheading:11753432-Cadmium,
pubmed-meshheading:11753432-Calcium,
pubmed-meshheading:11753432-Calorimetry, Differential Scanning,
pubmed-meshheading:11753432-Computer Simulation,
pubmed-meshheading:11753432-Crystallography, X-Ray,
pubmed-meshheading:11753432-Finland,
pubmed-meshheading:11753432-Gelsolin,
pubmed-meshheading:11753432-Humans,
pubmed-meshheading:11753432-Models, Molecular,
pubmed-meshheading:11753432-Mutation,
pubmed-meshheading:11753432-Protein Binding,
pubmed-meshheading:11753432-Protein Structure, Secondary,
pubmed-meshheading:11753432-Protein Structure, Tertiary,
pubmed-meshheading:11753432-Thermodynamics
|
| pubmed:year |
2002
|
| pubmed:articleTitle |
Loss of a metal-binding site in gelsolin leads to familial amyloidosis-Finnish type.
|
| pubmed:affiliation |
Cambridge University Chemical Laboratory and Cambridge Centre for Protein Engineering, MRC Centre, Hills Road, Cambridge CB2 2QH, UK.
|
| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
|